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Autophagy is an essential process by which cells break down their own components. Perhaps the most basic response of autophagy is to a cell's nutrient loss. However, in complex organisms, 'autophagy proteins' also protect a cell against infectious, autoimmune and inflammatory diseases.

The joints of children with the most common form of chronic inflammatory arthritis contain immune cells that resemble those of 90-year-olds, according to a new study led by researchers at Children's Hospital of Pittsburgh of UPMC and the University of Pittsburgh School of Medicine.

The findings, published in the August issue of Arthritis and Rheumatism, suggest that innovative treatment approaches could aim to prevent premature aging of immune cells.

Juvenile idiopathic arthritis, or JIA, is the most prevalent rheumatic condition in the world and affects one of every 1,000 children in the U.S., said senior researcher Abbe de Vallejo, Ph.D., associate professor of pediatrics and immunology, Pitt School of Medicine. It usually starts with a swollen ankle, knee or wrist that parents often assume is due to a minor injury sustained while playing.

"Untreated JIA has devastating consequences," Dr. de Vallejo said. "It can slow growth and, in extreme cases, the child can be physically disfigured. It's a degenerative disease that eats up the joints."

Doctors have long thought of JIA as an autoimmune disease, meaning the body attacks itself. But previous studies by Dr. de Vallejo of young adults with rheumatoid arthritis indicated that a certain population of cells present in the joint synovial fluid and blood displayed telltale signs of abnormal cell division and premature aging. His current team at Children's wanted to see if that was true in pediatric arthritis.

They examined immune cells called T-cells in the synovial fluid and blood from 98 children ages 1 to 17 and known to have JIA, as well as 46 blood samples from children who didn't have the disease. T-cells are the army of immune cells that eradicate infection, tumors and other dangerous agents to which people may be exposed.

The research team found about one-third of the T-cells of children with JIA had shortened telomeres and had reduced, or in some cases lost, the capacity to proliferate. Telomeres are the ends of chromosomes that don't code for proteins and, because they are not fully copied by enzyme mechanisms, are trimmed slightly during each DNA replication cycle. It is thought that aging occurs when the telomeres become too short for DNA replication and cell division to proceed normally.

"The T-cells of the children with JIA had very short telomeres, about the length we see in a 90-year-old or a young adult with rheumatoid arthritis. Those same T-cells express unusually high levels of several classic protein markers of cell aging and exhaustion," Dr. de Vallejo said. "These kids haven't lived long enough to have cells that look that old. This is the first indication that premature aging in occurring in this childhood condition."

In addition, the T-cells had become dysregulated, and their immune activity could be stimulated through atypical cell surface receptors. Much more must be learned about the unusual cells and about genetic mechanisms that might contribute to the development of JIA, Dr. de Vallejo said, but these findings could point the way to new therapies.

"JIA is typically treated with broad-spectrum drugs such as steroids and biologics that essentially paralyze the entire immune system, but only a third of the cells are affected and their abnormality seems to be premature aging, rather than autoimmune activity," he noted. "This study suggests cell-targeted treatments could be developed to prevent this premature immune aging."

Abstract
Objective
CD8+ T cells lacking CD28 were originally reported to be a characteristic feature of juvenile idiopathic arthritis (JIA), but the relevance of these unusual cells to this disease remains to be elucidated. Because of recent evidence that loss of CD28 cells is typical of terminally differentiated lymphocytes, the aim of this study was to examine functional subsets of CD8+ T cells in patients with JIA.

Methods
Blood and/or waste synovial fluid samples were collected from children with a definite diagnosis of JIA (n = 98). Deidentified peripheral blood (n = 33) and cord blood (n = 13) samples from healthy donors were also collected. CD8+ and CD4+ T cells were screened for novel receptors, and where indicated, bioassays were performed to determine the functional relevance of the identified receptor.

Results
JIA patients had a naive T cell compartment with shortened telomeres, and their entire T cell pool had reduced proliferative capacity. They had an overabundance of CD31+CD28nullCD8+ T cells, which was a significant feature of oligoarticular JIA (n = 62) as compared to polyarticular JIA (n = 36). CD31+ CD28nullCD8+ T cells had limited mitotic capacity and expressed high levels of the senescence antigens histone γH2AX and/or p16. Ligation of CD31, which was independent of the T cell receptor (TCR), sufficiently induced tyrosine phosphorylation, vesicle exocytosis, and production of interferon-γ and interleukin-10.

Conclusion
These data provide the first evidence of cell senescence, as represented by CD31+CD28null CD8+ T cells, in the pathophysiology of JIA. Activation of these unusual cells in a TCR-independent manner suggests that they are maladaptive and could be potential targets for immunotherapy.

Co-authors of the paper include other researchers from Children's Hospital of Pittsburgh of UPMC; Pitt School of Medicine; and the Mayo Clinic. The project was funded by the Nancy E. Taylor Foundation for Chronic Diseases, the Arthritis Foundation, and National Institutes of Health grant AR052282.

About Children's Hospital of Pittsburgh of UPMC
Renowned for its outstanding clinical services, research programs and medical education, Children's Hospital of Pittsburgh of UPMC has helped establish the standards of excellence in pediatric care. From ambulatory care to transplantation and cardiac care, talented and committed pediatric experts care for infants, children and adolescents who make more than 1 million visits to Children's and its many neighborhood locations each year. Children's also has been named consistently to several elite lists of pediatric health care facilities, including ranking 7th among children's hospitals and schools of medicine (FY 2012) in funding provided by the National Institutes of Health, and is one of 10 pediatric hospitals in the United States named to U.S. News & World Report's Honor Roll of America's "Best Children's Hospitals" for 2013-2014.

About the University of Pittsburgh Schools of the Health Sciences
The University of Pittsburgh Schools of the Health Sciences include the schools of Medicine, Nursing, Dental Medicine, Pharmacy, Health and Rehabilitation Sciences and the Graduate School of Public Health. The schools serve as the academic partner to the UPMC (University of Pittsburgh Medical Center). Together, their combined mission is to train tomorrow's health care specialists and biomedical scientists, engage in groundbreaking research that will advance understanding of the causes and treatments of disease and participate in the delivery of outstanding patient care. Since 1998, Pitt and its affiliated university faculty have ranked among the top 10 educational institutions in grant support from the National Institutes of Health. For additional information about the Schools of the Health Sciences, please visit http://www.health.pitt.edu.

Original press release:http://www.upmc.com/media/NewsReleases/2013/Pages/premature-aging-of-immune-cells-present-pediatrics-chronic-arthritis.aspx